Dopaminergic Inhibition Of Prolactin Secretion Research Articles

Status epilepticus and diabetes ketoacidosis: uncommon clinical presentations of acromegaly.

SummaryAcromegaly is a rare disease caused by hypersecretion of the growth hormone (GH). Most cases are caused by either pituitary microadenoma or macroadenoma. The GH producing tumors present with clinical manifestations of acromegaly due to excessive GH secretion or symptoms resulting from mass effects of the enlarging tumor. The physical changes are usually slow and, therefore, recognition of the disease is delayed. These adenomas are never malignant but can have significant morbidity and mortality. A subgroup of patients with acromegaly present with severe hyperglycemia resulting in diabetic ketoacidosis (DKA) which requires insulin. Rarely are pituitary tumors responsible for generalized convulsions except when they are too large. We hereby present two cases, the first is that of a 26-year-old female who presented with new onset status epilepticus, DKA with a 1-year history of diabetes mellitus (DM). On examination, she had clinical features of acromegaly. The second case is that of a 34-year-old female who presented with new onset status epilepticus, hyperglycemia with a history of recently diagnosed DM, and features of gigantism. In both cases, their diagnosis was confirmed by elevated serum GH and later by elevated insulin-like growth factor type 1 levels, and CT of the head demonstrating large pituitary macroadenoma. The importance of clinical history and examination, as well as investigations is vital in the recognition of acromegaly. The prognosis of acromegalic patients depends on early clinical recognition and tumor size reduction by either medical or surgical therapy.Learning pointsConditions such as status epilepticus and DKA may be clinical presentations in patients presenting with acromegaly.Seizures are rare in people with pituitary adenoma and typically occur when the tumor invades the suprasellar area due to mass effect on the brain.This article shows how best we were able to manage the acromegaly complications in a low resource setting.Hyperprolactinemia in acromegaly may be due to disruption of the normal dopaminergic inhibition of prolactin secretion due to mass effect of the macroadenoma, and around 25% of GH-secreting adenomas co-secrete prolactin.

Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes.

The hypothalamus contains the highest diversity of neurons in the brain. Many of these neurons can co-release neurotransmitters and neuropeptides in a use-dependent manner. Investigators have hitherto relied on candidate protein-based tools to correlate behavioral, endocrine and gender traits with hypothalamic neuron identity. Here we map neuronal identities in the hypothalamus by single-cell RNA sequencing. We distinguished 62 neuronal subtypes producing glutamatergic, dopaminergic or GABAergic markers for synaptic neurotransmission and harboring the ability to engage in task-dependent neurotransmitter switching. We identified dopamine neurons that uniquely coexpress the Onecut3 and Nmur2 genes, and placed these in the periventricular nucleus with many synaptic afferents arising from neuromedin S+ neurons of the suprachiasmatic nucleus. These neuroendocrine dopamine cells may contribute to the dopaminergic inhibition of prolactin secretion diurnally, as their neuromedin S+ inputs originate from neurons expressing Per2 and Per3 and their tyrosine hydroxylase phosphorylation is regulated in a circadian fashion. Overall, our catalog of neuronal subclasses provides new understanding of hypothalamic organization and function.

Macroprolactinemia in Patients Presenting With Stalk Compressing Masses

Introduction Decreased dopaminergic inhibition of prolactin secretion by hypothalamus or stalk compressive masses can induce hyperprolactinemia. Macroprolactin may be the dominant form of prolactin in any case of hyperprolactinemia. The aim of this study was to evaluate the association of macroprolactinemia in patients presenting with hyperprolactinemia caused by stalk compressive masses. Patients and Methods We evaluated a series of 37 patients with hyperprolactinemia because of hypothalamus or stalk compressive masses. In patients with significant hyperprolactinemia (>35 μg/L in women and >30 μg/L in men), serum prolactin measured again, after incubation with poly ethylene glycol (PEG). Macroprolactinemia was diagnosed if the serum prolactin after PEG was ≤40% of initial serum prolactin. In 2 patients with macroprolactinemia, prolactin measured again before and after PEG, 2 months after surgery. Results Serum prolactin was significantly high in 18 (48.6%) patients. Macroprolactinemia proved in 3 patients (8.1%) after PEG incubation. In 2 of 3 patients surgery was performed. Prolactin level decreased after surgery in them but not to normal levels. After PEG test macroprolactinemia persisted but monomeric prolactin decreased to normal level only in 1 patient with complete resection, but remained elevated in the second one with significant remnant. Conclusions Macroprolactinemia may be the cause of hyperprolactinemia in stalk compressive masses. Macroprolactin forms after production and release of monomeric form from the pituitary.

The Roles of Dopamine and the Neurointermediate Lobe of the Pituitary in the Regulation of Prolactin Secretion During Late Pregnancy in Rats

The major hypothalamic control over prolactin secretion from the anterior pituitary gland is inhibitory by means of dopamine released from tuberoinfundibular dopamine (TIDA) neurones. We have previously shown a dissociation between activity of TIDA neurones and prolactin secretion during late pregnancy, suggesting involvement of additional regulatory factors. The aim of the present study was to investigate the role of dopamine and the neurointermediate lobe (NIL) of the pituitary in the regulation of prolactin secretion during late pregnancy. To determine whether dopamine maintains inhibition of prolactin during late pregnancy, the D(2) receptor antagonist domperidone was administered at 12.00 h on days 18 and 21 of pregnancy. These times are characterized by high and low TIDA neuronal activity, respectively, and low prolactin secretion. Domperidone produced an immediate increase in plasma prolactin compared to vehicle-treated controls on both days 18 and 21. Thus, dopaminergic inhibition of prolactin secretion is maintained despite reduced TIDA neuronal activity at the end of pregnancy. The contribution of NIL-derived dopamine in regulating prolactin secretion was then examined by investigating the effect of surgical removal of the NIL. NIL removal produced significantly increased basal prolactin concentrations, indicating that dopamine from the NIL contributes to the suppression of prolactin before the antepartum prolactin surge. Furthermore, NIL removal also completely prevented the antepartum prolactin surge compared to sham-operated controls, which is consistent with the hypothesis that the NIL supplies a prolactin-releasing factor to the anterior pituitary to induce the antepartum prolactin surge.

Switch to quetiapine in antipsychotic agent-related hyperprolactinemia

Novel antipsychotics (clozapine, risperidone, olanzapine, quetiapine) are effective in treating psychotic symptoms, also in neurological disease. Hyperprolactinemia is a side effect related to antipsychotics that can cause galactorrhea, gynecomastia, amenorrhea, anovulation, impaired spermatogenesis, decreased libido and sexual arousal, impotence, and anorgasmia, consequent to removal of tonic dopaminergic inhibition of prolactin secretion via hypothalamic dopaminergic receptor blockade in the tuberoinfundibolar tract. Hyperprolactinemia occurs more frequently during treatment with risperidone and olanzapine compared with clozapine and quetiapine. The therapeutic algorithm to antipsychotic-relatedhyperprolactinemia is the following: reduction in antipsychotic dose, addition of cabergoline, bromocriptine, amantadine, and/or switch to another antipsychotic. We propose switching to quetiapine in symptomatic hyperprolactinemia related to antipsychotics and describe five cases.

Dopaminergic and opioidergic regulation of gonadotropin and prolactin release in stallions.

In the non-breeding season, LH release is reduced via dopaminergic systems in the ram. On the other hand, our previous studies demonstrated an opioidergic inhibition of LH release in stallions outside the breeding season. Thus, in the present study we investigated the dopaminergic regulation of LH and prolactin secretion in stallions, considering interactions between dopamine and opioids. To achieve this, stallions (n=8) were treated with the dopamine antagonist sulpiride (0.6 mg/kg), the opioid antagonist naloxone (0.5 mg/kg), sulpiride plus naloxone or saline in December, March and June. Two hours after the respective treatments, they received a GnRH agonist. Sulpiride induced a significant prolactin release which was most pronounced in December, indicating seasonal variations in the inhibition of prolactin secretion by dopaminergic systems. Prolactin concentrations were not changed by naloxone. Neither during nor outside the breeding season, a dopaminergic regulation of LH release could be demonstrated. In contrast, naloxone caused a significant (p < 0.05) LH release, confirming an opioidergic inhibition of LH release. In conclusion, opioidergic regulation of LH and dopaminergic inhibition of prolactin secretion undergo seasonal changes. Neither during nor outside the breeding season, dopaminergic effects on LH release exist in the stallion.

Effects of ovarian surgery on the dopaminergic and opioidergic control of gonadotropin and prolactin secretion in women with polycystic ovarian disease.

Ovarian surgery has been demonstrated as an effective means to establish regular menstrual cycles and resumption of ovulation in patients with polycystic ovarian disease (PCO). We questioned whether such reinstitution of menstrual cyclicity may be associated with changes in the opioidergic and dopaminergic activity known to be aberrant in these women. Opioidergic and dopaminergic tone was therefore assessed in patients with PCO before and after ovarian laser vaporization (n = 4) or classical ovarian wedge resection (n = 4). Blood samples for the determination of luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin were frequently obtained following opioidergic and/or dopaminergic antagonism affected by naloxone (4 mg i.v.) or metoclopramide (10 mg i.v.). In response to either surgical approach, circulating LH levels decreased (p < 0.01), while FSH concentrations remained unaltered. Further, LH and FSH concentrations did not noticeably change following challenges with naloxone or metoclopramide: this applied to conditions before and after ovarian surgery. Prolactin release in response to metoclopramide was markedly (p < 0.01) higher following ovarian surgery than before. Thus, both ovarian laser surgery and classical wedge resection can effectively restore normal menstrual cyclicity in PCO patients, although they failed to alter opioidergic and dopaminergic activity. Dopaminergic inhibition of prolactin secretion was further enhanced after ovarian surgery. These observations suggest that different modes of ovarian surgery are effective in influencing central gonadal control, but that the central opioidergic and dopaminergic control of gonadotropin and prolactin secretion remains unaffected by ovarian surgery in PCO women, even when menstrual cyclicity is resumed.

The effects of a dopamine antagonist on luteinizing hormone and prolactin release in women with anorexia nervosa and in normal controls

To evaluate the possible role of central dopaminergic suppression of gonadotropin secretion in the genesis of amenorrhea associated with anorexia nervosa (A.N.), a central D-2 dopamine receptor blocker was administered to 10 women with A.N. and 10 regularly menstruating age-matched controls. Serum prolactin and luteinizing hormone (LH) levels were measured at − 15, 0, 30, 60, 120, and 180 min after administration of metoclopramide (10 mg orally). Mean basal prolactin ( p < 0.001) and estradiol levels ( p < 0.02) were significantly lower in women with A.N. The prolactin response to metoclopramide was significantly impaired in women with anorexia nervosa. No correlation was found between the prolactin response and percentage ideal body weight. Basal and post-stimulation prolactin levels were correlated with estradiol levels. After adjusting for the effects of estradiol, significant differences between patients with A.N. and controls remained in prolactin levels at baseline ( p < 0.01), 120 min ( p < 0.02) and 180 min ( p < 0.05). Metoclopramide did not induce a significant rise in LH levels in either the A.N. or control groups. These data are consistent with central dopaminergic inhibition of prolactin secretion in anorexia nervosa but do not support the hypothesis that central dopaminergic inhibition is related to diminished LH release in this state.

In vitro and in vivo antagonistic regulation by estradiol and progesterone of the rat pituitary domperidone binding sites: correlation with ovarian steroid regulation of the dopaminergic inhibition of prolactin secretion in vitro.

The influences of in vivo and in vitro estradiol (E2) and progesterone (P) treatments on the characteristics of [3H]domperidone binding to intact and ovariectomized (OVX) rat pituitary membranes were analyzed and compared to the modulation by these steroids of dopamine (DA) inhibition of PRL secretion in vitro from intact and OVX rat pituitaries. Using intact rat pituitaries, high and low affinity binding sites for domperidone were detected; the dose-dependent DA inhibition curve of PRL secretion was biphasic (range, 10(-13) - 10(-10) M DA, IC50 = 6 X 10(-12) M; range, 10(-10) - 10(-6) M DA, IC50 = 2 X 10(-8) M). Using OVX rat pituitaries, only the high affinity sites for domperidone were detected, and the dose-dependent DA inhibition curve of PRL secretion was monophasic (range, 10(-10) - 10(-6) M DA, IC50 = 10(-8) M). E2 and P did not modify the characteristics of the high affinity sites either after in vivo treatment or when directly added to the in vitro binding assay. However, using in vivo and in vitro tests, a modulation of the low affinity sites by E2 and P was demonstrated. When E2 is in excess and P levels are low or undetectable, these sites are not detectable, and P is able to restore there presence. A parallelism has been established between this antagonistic E2 and P regulation and the modulation of DA inhibition of PRL secretion (range, 10(-13) - 10(-10) M DA). When intact rat pituitaries are perifused in the presence of 10(-8) M E2, the biphasic dose-dependent inhibition curve of the control is changed into the monophasic curve of the OVX rat pituitaries. Conversely, when OVX rat pituitaries are perifused in the presence of 10(-6) M P, the monophasic curve of the control is changed into the biphasic curve of the intact rat pituitaries. Thus, the DA inhibition in the range 10(-13) - 10(-10) M might result from an interaction between DA and the low affinity site for domperidone. In summary, the biological regulation of PRL by DA at the pituitary level may be mediated by two different DA sites, one being submitted to an antagonistic E2 and P regulation directly at the membrane level. The consequence of this regulation is that, whereas E2 decreases the sensitivity of the cell to DA, P is necessary for a normal DA response of the lactotroph.

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma

Role of defective dopaminergic inhibition of prolactin secretion in the pathogenesis of prolactinoma.

Prolactinomas pose an increasingly frequent therapeutic dilemma for the clinician. The neurosurgeon caring for the prolactinoma-bearing patient must stay abreast of the most current basic research concerning the pathogenesis of these often difficult tumors. A fascinating and dynamic line of research involves the possibility that prolactinomas arise secondary to a flaw in the normally inhibitory dopaminergic neurohypophyseal axis. The details of this hypothesis are presented, the current literature surrounding this topic is reviewed, and a brief synthesis of the available theoretical models of prolactinoma pathogenesis is provided.

The possible involvement of both calcium and cyclic AMP in the dopaminergic inhibition of prolactin secretion

Dopamine inhibited basal, TRH-, IBMX- and A23187- stimulated prolactin secretion from rat anterior pituitary cells. However, dopamine did not inhibit prolactin secretion stimulated by elevated K + concentrations. These data are interpreted in terms of dopaminergic inhibition of both cyclic AMP production and Ca 2+ influx through agonist-, but not voltage-, dependent Ca 2+ channels.

In vivo supersensitivity of the anterior pituitary of old female rats to dopaminergic inhibition of prolactin secretion.

Old female rats (20-27 months) were given acute administration of an indirectly acting dopamine (DA) agonist, nomifensine or scalar doses of the direct DA receptor agonist, bromocriptine. Young female rats (4-9 months) were used as controls. Nomifensine (10 mg/kg i.p.) decreased significantly basal prolactin (PRL) levels in young rats as in old rats. In young rats, bromocriptine decreased significantly basal PRL levels only at the dose of 0.5 mg/kg intraperitoneally, the doses of 0.1 and 0.02 mg/kg being ineffective. In contrast, in old rats administration of 0.02 mg/kg of bromocriptine consistently inhibited basal PRL levels and the maximum PRL-lowering effect was already evident at the dose of 0.1 mg/kg. These data indicate that the pituitary of old rats, due to the age-related removal of dopaminergic inputs from the tuberoinfundibular system, becomes supersensitive to direct dopaminergic stimulation. This phenomenon may explain the normal PRL responsiveness of old rats to nomifensine, despite defective tuberoinfundibular dopaminergic function.

Neuroendocrine evidence that tetrabenazine is a dopamine antagonist.

Tetrabenazine is considered to be a reserpine-like drug because of its ability to block dopamine storage in presynaptic vesicles. We used two methods to determine that tetrabenazine is also a dopamine antagonist. Tetrabenazine displaced the specific [3H]spiperone binding to the dopamine receptors of the anterior pituitary, the corpus striatum, and a transplantable rat pituitary tumor with values for 50% displacement (IC50) of about 15 microM. Under in vitro conditions, 0.5 to 10 microM tetrabenazine blocked dopaminergic inhibition of prolactin secretion from rat anterior pituitary glands. One, four, and twenty-four hours after a single tetrabenazine injection (30 mg/kg, ip), the serum prolactin changed from 22 +/- 9 ng/ml initially, to 450 +/- 52, 254.7 +/- 10.4, and 9.3 +/- 1.1 ng/ml, respectively. Pituitary glands of the treated rats incubated in vitro were refractory to dopaminergic inhibition of prolactin release to an extent that was maximal at one hour but inapparent by 24 hours after injection. In vivo and in vitro, tetrabenazine induces biological responses characteristic of a dopamine antagonist. These actions are independent of the reserpine-like properties of tetrabenazine. The unusual ability of tetrabenazine both to antagonize dopamine and to block presynaptic dopamine storage may provide a new tool for understanding the physiology of dopaminergic systems.

Tetrabenazine has properties of a dopamine receptor antagonist.

Tetrabenazine is considered to act in a manner similar to reserpine to reduce the involuntary movements of tardive dyskinesia or Huntington's disease and to improve psychoses. We determined that tetrabenazine also has properties of a dopamine receptor antagonist by testing the ability of tetrabenazine to block the inhibitory effect of dopamine on prolactin secretion from rat anterior pituitary glands in vitro and to displace 3H-spiperone binding to dopamine receptors in the pituitary, corpus striatum, and a rat transplantable prolactin-secreting tumor. Under in vitro conditions, 0.5 to 10 microM tetrabenazine directly blocked dopaminergic inhibition of prolactin secretion. Furthermore, 1 hour after tetrabenazine injection (30 mg/kg intraperitoneally) in vivo, when the serum prolactin had increased from 22 +/- 9 to 450 +/- 52 ng/ml (p less than 0.01), pituitary glands of the treated rats examined in vitro were refractory to dopaminergic inhibition of prolactin release. Tetrabenazine apparently interacts with the dopamine receptor because this drug displaced the dopamine antagonist 3H-spiperone from dopamine receptors of the three different tissues with an apparent inhibitory constant of about 5 microM. We conclude that tetrabenazine has biological and pharmacological properties typical of a dopamine receptor antagonist. These observations should stimulate a reevaluation of the mechanisms for the actions of tetrabenazine previously attributed exclusively to a "reserpine-like" effect.

Loss of central nervous system component of dopaminergic inhibition of prolactin secretion in patients with prolactin-secreting pituitary tumors.

The administration of l-dopa suppresses prolactin (PRL) secretion in normal subjects and in patients with hyperprolactinemia, although it is not known whether this effect, which requires the conversion of dopa to dopamine, is mediated peripherally or through the central nervous system. To distinguish between these effects, 10 normal subjects (6 male, 4 female) and 8 patients with hyperprolactinemia associated with pituitary tumors were given l-dopa, 0.5 g alone, or 0.1 g after a 24-h pretreatment with carbidopa, 50 mg every 6 h, which produces peripheral dopa decarboxylase inhibition. Similar degrees of PRL suppression were observed in normal subjects (basal plasma PRL 13+/-2 ng/ml) after l-dopa alone (48+/-4%) and after l-dopa plus carbidopa (58+/-6%). In patients with pituitary tumors and elevated plasma PRL (73+/-14 ng/ml), l-dopa alone led to PRL suppression comparable with that in normal subjects (47+/-6%). However, l-dopa plus carbidopa resulted in only minimal suppression of plasma PRL (19+/-4%) which was significantly less than after l-dopa alone (P < 0.001). Urinary homovanillic acid excretion, which reflected peripheral dopa decarboxylation was similar in controls and tumor patients after l-dopa both alone and after carbidopa pretreatment. Comparable suppression of PRL levels in response to a dopamine infusion (4 mug/kg per min for 3 h) was observed in controls and tumor patients. The results indicate that although peripheral conversion of exogenous dopa to dopamine can suppress PRL secretion, in normals, the central nervous system conversion of dopa to dopamine in the presence of peripheral dopa decarboxylase inhibition is sufficient to account for its PRL-suppressive effects. In contrast, patients with tumors, while retaining peripheral dopaminergic inhibitory effects on PRL secretion, exhibit a marked reduction of central dopaminergic inhibition of PRL secretion.